This is a proposal to investigate the molecular factors that affect the selectivity, efficacy, and potency of peptide and nonpeptide opioids. The main focus will be on the determination of preferred molecular conformations using the techniques of molecular mechanics (AMBER and MM2) and molecular dynamics (AMBER). The steric energies of possible conformers will be minimized with respect to all internal coordinates. The effect of polar and nonpolar environments on conformation will be examined by modifying the electrostatic interactions. Solvent effects will be simulated with Monte Carlo techniques. Due to the large number of variable dihedral angles for most opioid peptides, the focus will be on those which have the most severe steric constraints. These include morphiceptin (and its analogues) and cyclic peptides which have been shown to be selective for either the mu- or delta-receptors. The preferred geometries of the opioid peptides will be quantitatively superimposed with those potent nonpeptide opioids which contain two phenyl rings which may correspond to the two phenyl rings of the opioid peptides. These include phenazocine, an oripavine derivative, and fentanyl (and its derivatives). These comparisons should lead to the development of conformational models for mu- and delta-selective opioids. The objective of this research is to determine the three dimensional geometries that are responsible for the pharmacological activities of peptide and nonpeptide opioids. That is, the biologically active conformers which compounds the similar pharmacological profiles share with each other. The long range goal of this project is to achieve a better understanding of the relationship between the molecular structure of opioids and their pharmacological actions. This will be useful in the design of novel compounds which may have more selective actions and fewer undesirable side effects.